Because patients with rare familial homocystinuria who also carry factor V Leiden have an increased incidence of venous thromboembolism (VTE), we hypothesized an interrelation of moderate hyperhomocyst(e)inemia, factor V Leiden, and risk of VTE in the general population. In a large prospective cohort, we determined total homocysteine level and factor V Leiden mutation in baseline blood samples from 145 initially healthy men who subsequently developed VTE and among 646 men who remained free of vascular disease during a 10-year follow-up period. Hyperhomocyst(e)inemia was defined as a total homocysteine level above the 95th percentile (17.25 mol/L). Compared with men with normal total homocysteine levels, those with hyperhomocyst(e)inemia had no increase in risk of any VTE but were at increased risk of idiopathic VTE (relative risk [RR]=3.4, P=.002). Compared with men without the Leiden mutation, those with the mutation were at increased risk of developing any VTE (RR=2.3, P=.005) as well as idiopathic VTE (RR=3.6, P=.0002). Compared with men with neither abnormality, those affected by both disorders had a 10-fold increase in risk of idiopathic VTE (RR=21.8, P=.0004). Apparently healthy men with coexistent hyperhomocyst(e)inemia and Leiden mutation are at a substantially increased risk of developing future VTE's, particularly those events considered idiopathic. In these data, the risk of VTE among doubly affected individuals was far greater than the sum of the individual risks associated with either abnormality alone.